Genetic Variant NM_002676.3:c.739G>A (chr22-41577368-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002676.3(PMM1):c.739G>A(p.Val247Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,684 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V247L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PMM1
NM_002676.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.67

Publications

0 publications found

Variant links:

Genes affected

PMM1 (HGNC:9114): (phosphomannomutase 1) Phosphomannomutase catalyzes the conversion between D-mannose 6-phosphate and D-mannose 1-phosphate which is a substrate for GDP-mannose synthesis. GDP-mannose is used for synthesis of dolichol-phosphate-mannose, which is essential for N-linked glycosylation and thus the secretion of several glycoproteins as well as for the synthesis of glycosyl-phosphatidyl-inositol (GPI) anchored proteins. [provided by RefSeq, Jul 2008]

PMM1 links:

CSDC2 (HGNC:30359): (cold shock domain containing C2) Predicted to enable mRNA 3'-UTR binding activity. Predicted to be involved in regulation of mRNA stability. Predicted to be located in nucleus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

CSDC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002676.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM1	NM_002676.3	MANE Select	c.739G>A	p.Val247Met	missense	Exon 8 of 8	NP_002667.2	Q92871

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMM1	ENST00000216259.8	TSL:1 MANE Select	c.739G>A	p.Val247Met	missense	Exon 8 of 8	ENSP00000216259.7	Q92871
PMM1	ENST00000949539.1		c.973G>A	p.Val325Met	missense	Exon 10 of 10	ENSP00000619598.1
PMM1	ENST00000940470.1		c.868G>A	p.Val290Met	missense	Exon 9 of 9	ENSP00000610529.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460684

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726652

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.52

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

0.34

PhyloP100

5.7

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.59

REVEL

Uncertain

0.51

Sift

Benign

0.66

Sift4G

Benign

0.46

Polyphen

0.99

Vest4

0.35

MutPred

0.48

Gain of disorder (P = 0.0966)

MVP

1.0

MPC

0.42

ClinPred

0.72

GERP RS

5.5

Varity_R

0.19

gMVP

0.38

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over